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ABOUT THIS AUTHOR

Derek Lowe, an Arkansan by

birth, got his BA from Hendrix

College and his PhD in organic

chemistry from Duke before

spending time in Germany on a

Humboldt Fellowship on his

post-doc. He's worked for

several major pharmaceutical

companies since 1989 on drug

discovery projects against

schizophrenia, Alzheimer's,

diabetes, osteoporosis and

other diseases. To contact

Derek email him directly:

[email protected]

Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipel

May 11, 2012

Desperation In the Lab

Posted by Derek

You chemists may have really stretched things to get a reaction to work, but here's a good set of "Conditions You'll Probably

Enough to Try". Bone meal? Ground carrots? I think he has a point.

Comments (7) + TrackBacks (0) | Category: Life in the Drug Labs

Competitive Intelligence: Too Much or Too Little?

Posted by Derek

Drug companies are very attuned to c ompetitive intelligence. There's a lot of information sloshing around out t here, and you

attention to it. Publications in journals are probably the least of it - by the time something written up for publication from ins

it's either about to be on the drugstore shelves or it never will be at all. Patents are far more essential, and if you're going toshould watch the patent applications in your field.

But there's more. Meetings are a big source of disclosure, as witness the Wall Street frenzies around ASCO and the like. Talk

information that won't show up in the literature for a long time (if indeed it ever does). And there are plenty of other avenue

though, how much time and money do you want to spend on this sort of thing?

There are commercial services (such as Integrity) that monitor companies, compounds, and therapeutic areas in this fashion

sell you their services, which are not cheap. But figuring out the cost/benefit ratio isn't easy. My guess is that these things,

thought of as insurance. You're paying to make sure that something big doesn't happen that you're unware or (or unaware o

So here's a question for the readership: has competitive intelligence ever made a big difference for you? Positive and negativ

"I'm so glad we found out about X" versus "I really wish we'd known about Y". Any thoughts?

Comments (12) + TrackBacks (0) | Category: Drug Development

May 10, 2012

The World of Metal-Catalyzed Couplings

Posted by Derek

Here's an excellent article, with copious references, tracing the history of what we now know as the metal-catalyzed couplin

of Queen's University, Thomas Colacot (Johnson Matthey) and co-authors go back to the Wurtz and Glaser reactions of the

through the Ullmann reaction (1891, and still very much with us) and Kharasch and Cadiot-Chodkiewicz couplings (1940s) be

world of palladium with the Wacker oxidation.

Along the way, one learns that the discoverer of palladium (Wollaston) could never interest anyone in the metal, and almost

extracted was still sitting on the shelf, unsold, at his death. Time vindicated him, and how - it's now perhaps the most essen

world. The late 1960s were a turning point:

Entry of Richard Heck: Following post-doctoral studies, Heck accepted a position at Hercules Powder Co where he

freedom that is seldom experienced by the modern industrial chemist. Briefed with the task of doing something w

metals, Heck investigated the chemistry of cobalt carbonyl complexes. Although this work generated many inter

observations, finding profitable applications for his research proved difficult. Inspired by his colleague Pat Henry's

Wacker oxidation, Heck's attention turned in the direction of arylpalladium chemistry .

He tried Wacker-type conditions with other reagents around to try to intercept the palladium intermediate, and organomercu

immediate reaction. The story from there is a trip through a good swath of the periodic table, and the development of an aw

expertise in metal complexes. Enter then Mizoroki, Kumada, Sonogashira, Negishi, Stille, Suzuki and many others. It's a long,

paper should serve as the definitive overview, and an excellent look at how chemistry (and science in general) go about disc

things.

Comments (4) + TrackBacks (0) | Category: Chemical News


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Arena and Lorcaserin, Back at the FDA

Posted by Derek

For those of you following Arena Pharmaceuticals and their long-running efforts to get lorcaserin approved by the FDA, there

on that matter today. Adam Feuerstein is live-blogging the event here. The big issues, now with fresh data: tumors in rat m

valve damage, versus efficacy. The FDA has until June 27 to make a decision.

Comments (7) + TrackBacks (0) | Category: Diabetes and Obesity

The UK Goes Open-Access

Posted by Derek

More disruption in the scientific publishing model: the UK government has announced that it will set up an open-access syste

generated through its funding, similar to the system in the US. The details are still being worked out, and the government is

not "ruining the value provided by academic publishers", but it's that value that's at issue, isn't it?

A statement from Wiley said that "Publishers enable content digitisation, rigorous peer review, st rong editorial infrastructure

investment in an effec tive online platform for dissemination." And yes, they do those things. But how well do they do them?

them for the prices they charge? I'm glad that these arguments are finally out on the table.

Comments (6) + TrackBacks (0) | Category: The Scientific Literature

GSK Goes Hostile

Posted by Derek

I mentioned the other day that Human Genome Sc iences had turned down an offer from GSK, feeling that they c ould do bett

now's the time: GSK is now offering the same deal ($13/share) on the open market in a hostile takeover attempt. One of the

about that price, and now I guess we'll find out which one of them it is. . .

Comments (5) + TrackBacks (0) | Category: Business and Markets

May 9, 2012

One More on That Buckyball Longevity Paper

Posted by Derek

I've received another e- mail from Prof. Fathi Moussa, lead author of the C60 longevity paper that's been discussed around h

critiques that had shown up in the comments sections, and here's the reply:

An erratum with the r ight figures 3 and 4 will be published soon in Biomaterials. The right lifespan values after the

the treatment are given in the original text without any change. To sum it up, the extensions of lifespans are twe

and sixteen months with respect to water-treated controls and olive-oil-treated c ontrols, respectively.

Our original objective was not to study lifespan extension but the toxic effects of C60 at reiterated doses. Lifespa

C60 is not really surprising, all the more so as it had already been shown by others that some C60-derivatives can

lifespans in several experimental models, albeit moderately.

What is really surprising in our results is that C60 acts at very low doses, which means that the effect is very str

this effect lasts for a long time after the end of the administration. A possible explanation is that some C60 precip

the reticulo-endothelial system and then slowly dissolves and diffuses.

Of course we understand that non C60 specialist readers are incredulous about these results, as it could be expec

We hope now that others will try and confirm our results. If our results are confirmed by others, which we firmly

be then necessary to try to reproduce these experiments on bigger samples including other species and of course

the dose and the duration of the treatment.

I share that hope that others will try to confirm the results. It'll be a while, most likely, before we hear about anything in this

something comes up, I'll blog about it.

Comments (7) + TrackBacks (0) | Category: Aging and Lifespan

More Reaction Discovery (Now With Antibody Detection)

Posted by Derek

I've written here before about reaction discovery schemes, and the reaction to those reactions has been, well, mixed. I like

like them, but some other people are quite offended by the "random search" mentality behind these ideas.


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God of the Machine

Armavirumque

About Last Night

Well, prepare yourselves for another technology for exploring the wild blue yonder. A new paper inAngewandte Chemie from

sur Yvette, France) outlines an immunological detection scheme. They have antibodies to an imidazole derivative, and antibo

as well. So both structures are attached to a range of functional groups and combined with heat and/or metal catalysts to s

A sandwich assay at the end with the different antibodies gives you a yellow color only if a compound has been formed that

that is, if a coupling reaction of some sort has occurred.

They ran 3360 reactions, each on a 100 nmol scale (there's the sensitivity of the antibodies for you). Two new reactions we

isourea synthesis (which can lead to benzoxazoles) and an alkyne reaction leading to thiazole derivatives. Neither of those is

of organic chemistry ablaze, but as a proof of concept, I'm convinced that this technique can work. So what do you do with

One plan looks to be discovering new bioorthogonal reactions, couplings that can take place either inside or on the surface o

immunological detection is so sensitive that products can be teased out of all sorts of messy mixtures, apparently even cell ly

encourage them to try some other conditions, such as various photochemical setups, to see what might be out there - it's a

than copper-catalyzed coupling reactions.

Like it or not, I think we're going to be seeing more of this sort of work. We might as well make the most of it!

Comments (3) + TrackBacks (0) | Category: Chemical News

PhDs On Food Stamps?

Posted by Derek

A number of people have sent me this article about the number of people with Master's and PhD degrees who are receiving f

undeniable that the numbers have grown, I'd ask for everyone to keep their statistical glasses on. According to the chart at

percentage of doctorate holders receiving assistance went from 0.05% in 2007 to 0.15% in 2010. (For MS/MA degree holder

1.3% over that same time).

So it can't be said that this is a widespread phenomenon. One would also want to see the numbers broken down by age coho

field of study. The examples in the article are all history and English types. Also, if those figures are correct, the headline cou

read "Master's Degree Holders Ten Times More Likely To Be On Food Stamps".

Honestly, the number I find most alarming in that chart is the total number of advanced degree holders. We went from 20 mi

in 2010 - two million more in only three years? The population of the country went from 301 million to 313 million during that

good crop of degree holders. Given what the economy has been like during that period, I'm surprised the food stamp figures

Looking at advanced degrees as a percentage of the population, we have 4.3% in 1970, 7.2% in 1980, 8.8% in 1990, 8.6% i

a loss to explain), and 10.6% in 2009. Those figures don't quite add up with the ones in the food stamp article, but the trend

direction. We have figures in the growth in bachelor's degree or higher going back to 1940, and they show the relentless upt

So it shouldn't come as a surprise that well-educated people are participating more in some of the downsides that hit the res

Well-educated people are becoming more and more ofthe population.

Comments (19) + TrackBacks (0) | Category: Business and Markets | General Scientific News | Graduate Sc hool

May 8, 2012

Laboratory Crime, Not Paying

Posted by Derek

You'll remember the Sanofi chemist who was caught selling proprietary compounds through her own Chinese outsourcing com

Pharmalot, comes word that Yuan Li has been sentenced to 18 months in prison, along with paying $131,000 in restitution. T

plan has turned out not to perform up to expectations. Perhaps this example will keep another fool from trying it?

Comments (13) + TrackBacks (0) | Category: The Dark Side

Buckyball Longevity: The Lead Author Replies

Posted by Derek

I've received a reply from Dr. Fathi Moussa at Universit Paris-Sud, lead author of t he C60 longevity paper that I blogged ab

out to have a duplicat ed figure. With permission, here are the main points of the e-mail:

Of course, you are right: in the published figure 4 the GAog and GAip panels are identical. These two panels were

represent the well-known effect of intra-peritoneally (i.p.) administered CCl4 on rat livers. The mistake was obvio

fact that the pretreatment of control animals with water either orally (GAog) or i.p. (GAip) cannot influence the e

on livers. Therefore the effects on liver are identical and the corresponding figures are expected to be closely alik

sent to the Editor an erratum that will be published soon.

We are very grateful to you for warning us about this figure. We are very furious against ourselves. We still do no

how such error could have escaped our notice during the revision process. While this mistake has not any influenc


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validity of the results described in the text, this could raise a certain amount of doubt over the work. The extensi

lifespan of rats is real and we fear that our error could delay or even prevent control experiments we are expecti

by others.

We have published on C60 toxicity since 1995 and all our results have been confirmed by several independent team

That point in the second paragraph is an important one: if these results are real, they're quite important and interesting. But

scientific result, they won't be accepted as real until they've been replicated, and replicating this experiment is already a sub

mistake with the figures doesn't help to get these started. (I should note that I've also called the authors' attention to the

the comments).

My hope is that other groups studying longevity effects in rodents (and having already made the commitment that entails) w

arm to their experiments as a comparison.


May 7, 2012

More Details

Posted by Derek

A couple of notes: in the previous post, I forgot to include the link to Wavefunction's article on the "negative rate constant"

well worth a look.

And I wanted to note that the post that discusses the Dobson and Kell theories about how compounds make their way into

from Douglas Kell himself, which is also worth a look if you're into this topic.

Comments (4) + TrackBacks (0) | Category: Blog Housekeeping

You're A Peer, Too, You Know

Posted by Derek

Over at The Curious Wavefunction, there's a great post looking back at the infamous "negative rate constant" affair (Breslow

you're not familiar with that one, give it a look. I remember this one while it was going on, and in retrospect, you have to im

been like if there had been a chemical blog world at the time. It's an extraordinary chapter in chemical (and chemical literatu

To that end, there's this opinion piece from yesterday's New York Times. Author Jack Hitt is talking about the tail of commen

notable article, in any field:

Almost any ar ticle worth reading these days generates some version of this long tail of commentary. Depending on whethe

these comments can range from blistering flameouts to smart factual correct ions to full-on challenges to the very heart o

.

. . .the comments sec tion of any engaging article is almost as necessary a read as the piece itself if you want to know h

received the article and how those outsiders processed the news (and maybe to enjoy some nasty snark from the trolls).

Should this part of every contemporary article be curated and edited, almost like the piece itself? Should it have a name? S

linked to the original article or summarized at the top? By now, readers understand that the definitive copy of any article

paper but the online copy, prec isely because its the version thats been read and mauled and annotated by readers. (If a b

written in as I was always told then maybe an article is not published until its been commented upon.) Writers know t

edition of any article is little more than a trophy version, the equivalent of a diploma or certificate of merit suitable for fr

I think this is exactly what science is about, and exactly what it needs. People should be able to read the latest results, add

criticisms to them, and those comments in turn should also be available for everyone to see. There's going to be noise in the

noise as the price that gets paid for figuring things out more quickly and more completely than we ever could before. As far "peer" in "peer review" means "Everyone who can read and understand the paper".


The CETP Saga Continues (And It's Not Getting More Entertaining)

Posted by Derek

Roche has halted trials of its CETP inhibitor dalcetrapib. Many will remember the Pfizer compound in this c lass, torcetrapib, w

catastrophically in Phase III back in 2006. In that case, deaths in the treatment group were higher than the placebo group,

screeching halt every time. The generally accepted story is that the compound's effects on blood pressure (and possibly ele

its beneficial effects on lipoproteins. But was torcetrapib actually working? It certainly raised HDL levels - but is that enough

You have to wonder. Dalcetrapib wasn't taken out by toxicity - it was dropped because of "a lack of clinically meaningful effi

Phase II trials seems to have shown no beneficial outcome in cardiovascular mortality and mobidity. So what is it that we do


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about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess.

Two companies that are very, very much pondering that question are Merck and Eli Lilly, both with competing CETP inhibitor

statement from each of them that they continue to have confidence in their clinical candidates. But behind the scenes, expe

re-evaluation.

Comments (31) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials

May 4, 2012

Cytotoxic? You Bet!

Posted by Derek

Now these are the funkiest structures I've seen in quite a while. I won't spoil the surprise; if you're an organic chemist, go a

link. This is one of those "No one's made compounds like this, so let's see if they do anything" papers, and I'd say that if you

of thing, you should go pretty far off the beaten path. That they have.

These compounds are - not surprisingly - said to be cytotoxic, with activity against a range of cancer cell lines. A couple of

paper, and I haven't found any normalcells used as controls for all that cytotoxicity. Sad to say, the betting would be that

But at least I've seen a class of compounds that I'll bet has never made it intoJ. Med. Chem. before.

Comments (28) + TrackBacks (0) | Category: Cancer | Chemical News

Benlysta's Adventures In the Real World

Posted by Derek

Benlysta got approved for lupus last year, as the first new drug in the field in decades. But as noted at the time, it didn't ex

at the FDA, nor in the clinic. Now it's having a rough time in Europe, which makes things interesting for both Human Genome

partners at GlaxoSmithKline.

Both the British (NICE) and German (IQWiG) agenc ies responsible for assessing the c ost/benefit of new drugs have recomme

use. This adds some drama to GSK's recent offer of $2.6 billion for HGSI, which the smaller company turned down out of han

bid seems to be based on the market potential of Benlysta, but the arguing has begun over how realistic those hopes are. Th

that gets settled with a sales price - or perhaps, in this case, just an upper bound. . .


GSK with AstraZeneca?

Posted by Derek

Here's a Reuters headline for you: "GSK reject s idea of buying AstraZeneca".

In other news, Delta Airlines has rejected the idea of making its new fleet of long-range passenger jets out of bamboo and s

There are also reports this morning that Burger King has rejected the idea of buying Birkenstock and cramming their sandals i

hamburger patties. More business news as it become available.


May 3, 2012

The Biotech Class of the Early 90s

Posted by Derek

Here's an excellent piece by venture capital guy Bruce Booth, looking back at the heady days of 1991-1994. I can tell you th

heady in Big Pharma, but there were a lot of startups coming along. Included are some really big names of today, but also a

even remembers any more. And how have investors fared? That depends:

Only a subset of the 1991-1994 IPO window have accrued real value over time. There were certainly a few big win

Gilead probably being the biggest, up over 100x since its IPO in 1992. MedImmune also fared quite well with its $

(though AZ is not thrilled about it now), and Vertex is up 10x.

But lets take the prior two examples, Isis and Amylin, which represent successful 20-year old mid-cap biotechs

gone from preclinical stage companies around their IPOs to having products launched or filed with the FDA. But th

really created any shareholder value over 20 years. Isis today trades at $8 per share, but it went public at $10 p

Amylin went out at $14, but c losed on the end of its first day of trading in 1992 at $21 per share. It now trades a

20 years, these companies (and many, many others in the 1991-1994 cohort) have underperformed not only all m

indices, but also treasury bills, and consumed billions in equity capital. And recall that many more companies from

probably at least half, ended up dying long whimpering deaths like long-forgott en Autoimmune Inc and Alpha-Beta


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And that 's a big reason why you don't see so many big biotech/small pharma IPOs any more. The markets are a different pla

The current reality, shaped by a c ouple decades of lackluster performance, is that the public markets arent open

biotech. While they are much less tolerant of the value-destroying tactics of the past (which is a good thing), the

the bar so high as to discourage even great, innovative companies from considering it as a viable option. In this n

old company building models just dont work: its hard to back a startup today with an investment thesis around

the next Gilead the capital markets are just so different.

Small companies have to act differently, raise money differently, and sell themselves differently these days. Stay private, do

virtually/outsourced, sell out to Big Pharma earlier than before. . .it's worth another post or two to talk about some of those

Have an IPO!" one isn't going to be on the list. Not for some t ime to come, anyway.

Comments (10) + TrackBacks (0) | Category: Business and Markets | Drug Industry History

A Long-Delayed COX2 Issue Gets Settled - For $450 Million?

Posted by Derek

Has the last shot been fired, very quietly, in the COX-2 discovery wars? Here's the background, in which some readers of thi

participated at various times. Once it was worked out t hat t he nonsteroidal antiinflammatory drugs (aspirin, ibuprofen et al.)

enzyme cyclooxygenase, it began to seem likely that there were other forms of the enzyme as well. But for a while, no one c

one. That changed in the early 1990s, when Harvey Herschman at UCLA reported the mouse COX2 gene. The human analog

the heels of that one, with priority usually given to Dan Simmons of BYU, with Donald Young of the University of Rochester th

same time.

The Rochester story is one that many readers will be familiar with. The university, famously, obtained a patent for compound

therapeutic effect through inhibition of COX-2, without specifying what compounds those might be. They did not, in fact, ha

any hints about what they'd look like, and this is what sank them in the end when the university lost its case against Searle

fulfilling the "written description" requirement.

But there was legal action on the BYU end of things, too. Simmons and the university filed suit several years ago, saying tha

into a contract with Monsanto in 1991 to discover COX2 inhibitors. The suit claimed that Monsanto had (wrongly) advised Sim

patent on his discoveries, and had also reversed course, terminating the deal to concentrate on the company's internal effor

obtained what it needed from the Simmons work.

That takes us to the tangled origin of the COX2 chemical matter. The progenitor compound is generally taken to be DuP-697

and investigated before the COX-2 enzyme was even c haracterized. The compound had a strong antiinflammatory profile wh

different from the NSAIDS, which led to strong suspicions that it was indeed acting through the putative "other cyclooxygen

once the enzyme was discovered, and a look at its structure versus the marketed drugs shows that it was a robust series of

One big difference between the BYU case and the Rochester case was the Simmons did indeed have a contract, and it was

formed the basis for t he suit. The legal maneuverings have been going on for several years now. But now Pfizer has issued a

they have reached "an amicable settlement on confidential terms". The only real detail given is that they're going to establis

at BYU in recognition of his work.

But there may be more to it than that. Pfizer has also reported taking a $450 million charge against earnings related t o this w

certainly makes one think of Latin sayings, among thempost hoc , ergo propter hocand especially quid pro quo. We may no

since part of the deal would presumably include not releasing them. But it looks like a substantial sum has changed hands.

Comments (12) + TrackBacks (0) | Category: Drug Development | Drug Industry History | Patents and IP

May 2, 2012

Resveratrol Explained. A Little Bit.

Posted by Derek

There's a new paper out in Cell Metabolism on resveratrol and SIRT1, and t he press release from Elsevier (Cell Press) is just

"Study resolves controversy on life-extending red wine ingredient, restores hope for anti-aging pill", says the headline, but b

is going to do that. (This entry has links back to some of the history of the compound and the target, as covered here, but

indeed). The EmbargoWatch web site calls it a "truly appalling" press release, and while I can't disagree with that , I don't th

out: a lot of press releases are appalling.

And I disagree with them when they say that studies like this "probably don't deserve any coverage at all". It's actually a ver

even if it 's not going to resolve any major controversies all by itself. It's from David Sinclair and co-workers (a large internat

presents the results of a long-running effort to see if what resveratrol does in animals that don't have the SIRT1 protein at a

experiment, which cuts right to the question of whether resveratrol's effects are SIRT1-driven or not. Problem is, the traditio

model is almost always embryonic lethal in that case, so it's not so simple that generate such animals. The team was able to

body conditional knockout adult mice, though, and set about dosing them with resveratrol to see what happened then.

Well, quite a few things did. From what I c an see, the marquee items are these: normal mice fed a high-fat regimen showed

mitochondria when iven resveratrol, but the knockouts didn't, so that mi ht be a clear connect ion to SIRT1. Resveratrol's e


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be SIRT1-dependent (t here are several links in this post about that connection, some of which led to papers that hypothesiz

effect). But resveratrol treatment had good effects on glucose levels in mice, whether or not they had SIRT1 present, so tha

through some other pathway.

Sinclair's quoted in this Nature News piece as saying that this reflects the nature of resveratrol as a compound. Resveratro

very non-specific", he says. I think that's a very fair characterization, which is one of the reasons why I wouldn't take it my

interesting light on the 2010 controversy when two former Sirtris executives set up their own reveratrol distribution effort, t

It would be quite interesting, for the sheer science of it, to take one of the later (apparently cleaner and more targeted) SIR

that have come out of the GSK/Sirtris work and run it through the same animal model. You might expect the same sorts of S

perhaps much less of an effect on blood glucose, if that's really some off-target resveratrol thing. But since we're talking abo

here, prediction is a chancy business. I wonder if this experiment is being done somewhere?


May 1, 2012

Flip That Glucose, Please

Posted by Derek

Just another nitpicking note: if you're going to publish a paper on glucose conjugates of drugs (aspirin, in this case), you mig

draw the glucose as the correct enantiomer. I had to do a little head-scratching with this one, since the sugar ring is drawn

no carbohydrate chemist would ever use, but as far as I can tell, that's L-glucose instead of D. . .

This is not as big a deal in the grand scheme of things, but it particularly gets to me, as someone who worked with sugars as

for 4 1/2 years. And then, every chemical drawing program extant will draw you the correct stereochemistry. . .


Chemists and Biologists, In Detail

Posted by Derek

Let's f ile this one under "Cultural Differences Between Chemists and Biologists". Have any of my chemistry colleagues out the

in presentation detail between the two disciplines?

It's struck me several t imes over t he years. Biologists seem, on average, to go into much more granular detail about their ex

presenting to a mixed audience than do most chemists. Buffers, buffers that worked a little better, buffers that worked a bit

sizing column, western blot after western blot. The usual chemistry comment was always "Hey, I don't show pictures of my T

eventually I suppose we'll need to come up with another line as LC/MS takes over the world.

Even presenting among their own tribe, most chemists don't (to me) seem to go to the level of detail that I often see from p

or pharmacologists. My theory is that most forms of biology st ill have so many hidden variables in them (since it's an intrinsic

less understood science) that all the details need to be specified. Organic chemistry, for all its troubles, still tends to be mor

average, than molecular biology, and at a less picky level of detail

That's why chemists don't often feel the need to go into details even in a room full of chemists: "We had the bromide, so we

product s, and then we made these by reductive amination. . ."substitutes for "We had the aryl bromide, so we reacted it

acids under palladium-catalyzed coupling conditions to give these products, each of which still has the aldehyde in the 3-po

by chromatography in an ethyl acetate/hexane gradient over 8-gram ISCO silica gel cartridges. We then reacted them with

sodium triacetoxyborohydride in dichloromethane at room temperature, followed by a chromatography in 1 to 5% methano

Each of those steps has plenty of other options - different reagent combinations, solvents, etc., and if some colleague need

work, they'll check your notebook or ask you "Hey, what did you guys use for those Suzukis? Dppf? Yuck."

We certainly won't go into that level of detail in a room half full of biologists - it's mostly "We made these, and these, and th

everyone. No TLC plates, no LC/MS traces, no NMR spectra. But they're available if you want 'em.

Comments (60) + TrackBacks (0) | Category: Life in the Drug Labs

Regulatory Hurdles

Posted by Derek

John LaMattina has a good piece up on the FDA, where they might be trying to have it both ways. About a recent speech by

has this:

But Dr. Woodcock begins to stray into areas where I think she is off base. For one thing, she asserts that many l

[clinical] failures are due to efficacy problems. Thats not exactly true. It is only when companies take compoun

stage development with little or poor proof-of-concept data where this happens. The majority of phase 3 clinical

due to unforeseen, unpredicted side-effects or else due to finding that, in direct comparison to existing therapy, t


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. .

evaluative tools, new methodologies that can bett er predict the performance of a compound in late stage st ud

Of course, those tools are a good idea, and would be worth a lot (which is why everyone's been spending time and money tr

the FDA will not approve drugs based on them. They probably shouldn't - as LaMattina says, there have been quite a few dru

looked like they would work based on one secondary endpoint or another, only to come up short in the real world. Woodcock

approaches, but they won't necessarily shorten the time until approval. The hope is that they'll save time and money anothe

projects earlier, with some hope of being right. Anything that spares us an unnecessary Phase II, or especially an unnecessa

thing. But the eventual drug is going to have to jump through all the hoops, same as before.

Comments (9) + TrackBacks (0) | Category: Regulatory Affairs

April 30, 2012

India's First Drug Isn't India's First Drug

Posted by Derek

There have been a number ofheadlines the last few days about Ranbaxy's Synriam, an antimalarial that's being touted as th

developed inside the Indian pharma industry (and Ranbaxy as the first Indian company to do it).

But that's not quite true, as this post from The Allotrope makes c lear. (Its author, Akshat Rathi, found one of my posts whe

the story). Yes, Synriam is a mixture of a known antimalarial (piperaquine) and arterolane. And arterolane was definitely not

was part of a joint effort from the US, UK, Australia, and Switzerland, coordinated by the Swiss-based Medicines for Malaria V

Ranbaxy did take on the late-stage development of this drug combination, after MMV backed out due to no-so-impressive pe

As Rathi puts it:

Although Synriam does not qualify as Indias first new drug (because none of its ac tive ingredients were wholly d

India), Ranbaxy deserves credit for being the first Indian pharmaceutical company to launch an NCE before it was

anywhere else in the world.

And that's something that not many countries have done. I just wish that Ranbaxy were a little more honest about that in th

Comments (8) + TrackBacks (0) | Category: Drug Development | Infectious Diseases

AstraZeneca Shuffles the Top Cards

Posted by Derek

So Ast raZeneca's CEO is leaving. This wasn't necessary a voluntary move, but if it was, I don't blame him. I would have som

sticking around, too. (Ifreports of David Brennan's severance pac kage have any t ruth in them, though, he'll have some time

next.)The company has major problems in its drug pipeline, has had major problems for a long time now, and no obvious fixestake years of sustained effort.

Time for a reprise of this chart:


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That's the revenue coming in from existing drugs, and there's not much that bids to replace it, either. Note, again, that Eli Li

very similar fix. I would not expect things there to go smoothly over the next few years, either.


April 27, 2012

How Do Drugs Get Into Cells? A Vicious Debate.

Posted by Derek

So how do drug molecules (and others) get into cells, anyway? There are two broad answers: they just sort of slide in throug

their own (passive diffusion), or they're taken up by pores and proteins built for bringing things in (active transport). I've alw

believed) that both processes can be operating in most situations. If the properties of your drug molecule stray too far out o

example, your cell ac tivity tends t o drop, presumably because it's no longer diffusing past the c ell membranes. There are oth

can prove that you're hitching a ride on active transport proteins, by administering a known inhibitor of one of these system

your compound suddenly become inact ive, or by simply overloading and saturating the transporter.

There's another opinion, though, that's been advanced by Paul Dobson and Douglas Kell at Manchester, and co-workers. The

mediated t ransport is the norm, and that passive diffusion is hardly important at all. This has been received with varying deg

people seem to find it a compelling idea, while others regard it as eccentric at best. The case was made a few years ago in

Discovery, and again more recently in Drug Discovery Today:

All cells necessarily c ontain tens, if not hundreds, of carriers for nutrients and intermediary metabolites, and the

codes for more than 1000 carriers of various kinds. Here, we illustrate using a typical literature example the wides

erroneous nature of the assumption that the background or passive permeability to drugs occurs in the absence

Comparison of the rate of drug transport in natural versus artificial membranes shows discrepancies in absolute m

100-fold or more, with the carrier-containing cells showing the greater permeability. Expression profiling data sho

which carriers are expressed in which tissues. The recognition that drugs necessarily require carriers for uptake i

provides many opportunities for improving the effec tiveness of the drug discovery process.

That's one of those death-or-glory statements: if it's right, a lot of us have been thinking about these things the wrong way

some very important things about drug discovery as well. But is it? There's a rebuttal paper out in Drug Discovery Todaytha

defense. It 's by a long list of pharmacokinetics and pharmacology folks from industry and academia, and has t he air of "Let's

and for all" about it:

Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and

discussed to refute t he recently proposed theory that drug transport is CM-only and that new t ransporters will b

that possess t ransport charact eristics asc ribed to passive diffusion. Misconceptions and faulty speculations are a

provide reliable guidance on choosing appropriate tools for drug design and optimization.

Fighting words! More of those occur in the body of t he manuscript, phrases like "scientifically unsound", "potentially misleadi

speculation rather than experimental evidence". Here's a rundown of the arguments, but if you don't read the paper, you'll m

of teeth being ground together.

Kell and Dobson et al. believe that cell membrane have more protein in them, and less lipid, than is commonly thought, which

for lots of protein transport/not a lot of lipid diffusion. But this paper says that their figures are incorrect and have been misi

assertion is that artificial lipid membranes tend to have many transient aqueous pores in them, which make them look more p

are. This paper goes to some length to refute this, citing a good deal of prior art with examples of things which should have

membranes (but don't), and also find fault with the literature that K-D used to back up their own proposal.

This latest paper then goes on to show many examples of non-saturatable passive diffusion, as opposed to active transport,

overloaded. Another big argument is over the agreement between different cell layer models of permeability. Two of the big o

MDCK cells, but (as all working medicinal chemists know) the permeability values between these two don't always agree, eithwith the situation in living systems. Kell and Dobson adduce this as showing the differences between the various transporter

this rebuttal points out that there are a lot of experimental differences between literature Caco-2 and MDCK assays that can

around. Their take is that the two assays actually agree pretty well, all things considered, and that if transporters were the

numbers would be still farther apart.

The blood-brain barrier is a big point of contention between these two camps. This latest paper cites a large pile of literature

physical properties (molecular weight, logP) account for most successful approaches to getting compounds into the brain, co

diffusion, while examples of using active transport are much more scarce. That leads into one of the biggest K-D points, whic

the ones that drives the existing pharmacokinetics community wildest: the assertion that thousands of transport proteins rem

characterized, and that these will come to be seen as the dominant players compared to passive mechanisms. The counterar

these, as far as we can tell to date, are selective for much smaller and more water-soluble substances than typical drug mo

metal ions to things like glycerol and urea), and are unlikely to be important for most pharmaceut icals.

Relying on as-yet-uncharacterized transporters to save one's argument is a habit that really gets on the nerves of the Kell-D

" "


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s paper ca s pure specua on w ou sc en c ass or ev ence , w c s a ou as nas y as we ge n e e c n ca

interested readers to read both sides of the argument and make up their own minds. As for me, I fall about 80% toward the

there are probably important transporters that are messing with our drug concentrations and that we haven't yet appreciate

imagine that that's the whole story, nor that there's no such thing as passive diffusion. Thoughts?

Comments (33) + TrackBacks (0) | Category: Drug Assays | Pharma 101 | Pharmacokinetics

Different Worlds: A Last DHFR Paper Thought

Posted by Derek

Inspired by a discussion with a colleague, I'm going to take one more crack at the recent discussion here about the J. Med.

Those of you with an interest in the topic, read on. Those whose interest has waned, or who never had much interest to sta

other topics are coming.

It's clear that many people were disappointed with my take on this paper, and my handling of the whole issue. Let me state

the biology aspects of this one thoroughly, through carelessness, and I definitely owe this apology to the authors of the pap

this site) for that.

Of course, that's not the only arguable thing about the way I handled this one. As I spent paragraphs rambling on about in y

chemical aspect to the whole issue as well, and that's what caught my eye to start with. I think one of the things that got

one is two different ways of looking at the world. I'll explain what I mean, and you can judge for yourself if I'm making any se

The authors of the paper (and its reviewer who commented here) are interested in D67 dihydrofolate reductase, from a biolo

perspective. From this viewpoint - and it's a perfectly tenable one - the important thing is that D67 DHFR is an unusual and i

problem in bacterial resistance, interesting in its own right as a protein with an odd binding site, and for all that, still has no

inhibitors. Anything that advances the understanding of the enzyme and points toward a useful inhibitor of it is therefore a g

publishing inJ. Med. Chem., too.

I come in from a different angle. As someone who's done fragment-based drug discovery and takes a professional interest in

new paper using the technique. In this case, I gave the target much too cursory a look, and filed it as "DHFR, bacterial enzy

structures known". In other words, a perfectly reasonable candidate for FBDD as we know it. Once I'd decided that this was

of something I already have experience with, I turned my attent ion to how the fragment work was done. By doing so, I miss

of the DHFR enzyme, which means, to people in the first camp, that I whiffed on the most important part of the entire thing

frustration as I brushed that off like a small detail and went on to what (to them) were secondary matters.

But here's where my view of the world comes in. As a drug discovery guy, when I read a paper inJ. Med. Chem., I'd like to s

medicinal chemistry of the topic. That was the thrust of my blog post yesterday: that I found the med-chem parts of the pa

that the application of fragment-based techniques seemed to me to have gone completely off track. (I havne't mentioned th

aspects of the paper, as Teddy Z did at Practical Fragments, but I also found those parts adding nothing to the worth of the

The most potent compounds in the paper seem, to me, to be the sort that are very unlikely to lead to anything, and are unli

in a cellular environment. If the paper's starting fragment hits are real (which is not something that 's necessarily been proveyesterday's post), then it seems to me that everything interesting and useful about them is being thrown away as the paper

point of view, things are basically the opposite - the paper gets better and better as the compounds get more potent.

But here's where, perhaps, the two viewpoints I spoke of earlier might find something in common. If you believe that the imp

selective inhibitors of D67 DHFR have finally been discovered, then you should want these to be as potent and selective as p

possible in a variety of assays. This, I think, is what's in danger of being missed. I think that a fragment-based effort should

much more potent c hemical matter than these compounds, with less problematic structures, which are more likely to be usef

I'll finish up by illustrating the different angles as starkly as I can. The authors of this paper have, in one view of the world, c

fragment screen against an important enzyme, discovered the first-ever selective inhibitors of it, and have published these r

journal: a succ ess by any standard. From my end, if I were to lead a drug discovery team against the same enzyme, I might

fragment hits the authors did, since I know that some of these are in the collections I use. But if I proceeded in the same fas

prosecuting these hit compounds in the same way, I would, to be completely honest about it, face some very harsh question

in the same fashion, came up with the same final compounds, and presented them as the results of my team's work, I would

being fired. Different worlds.

Update: Prof. Pelletier sends the following:

I certainly have been following this with interest, and learning much from it not just science.

Throughout the week, I have appreciated your civil tone many thanks. I willingly accept your apology, just as I accept th

that will improve our future work. I think your two-worlds point of view smacks of truth. The bottom line from my point of

collaboration with a real fragment library: if anyone is interested in making this better, they should contact me. Id be delig

than what can be scavenged from neighbouring labs in an academic setting.

Your bloggers response to this come-and-go was fascinating: the process was admired to an extent that surprised me. A n

point out that there are currently few oc currences of open exchange on t hese blogs and sorry to disappoint hard-core bl

endear me to the blogging process. I dont blog because I cant stand anonymous, frequently disrespectful and sometimes

comments. I nonetheless hope that this will open the door to a more transparent blogging process in the long run.


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For any who care, I am brave, not at all desperate, and definitely a woman. ; )

If you feel any of this would be of interest for your blog, please feel free to post. Thanks for seeing this through rather than

Comments (21) + TrackBacks (0) | Category: Academia (vs. Industry) | The Scientific Literature

April 26, 2012

Elsevier Picks Up the Pace

Posted by Derek

So perhaps I should rethink all those nasty things I've been saying about Elsevier journals. Here's someone who submitted a Instruments and Methods on a Friday evening, and got it accepted - with two referee reports, yet - on Monday morning. Ho

say? That's what this author is wondering, too. . .


April 25, 2012

DHFR Inhibitors Revisited: A Word From the Authors (and Reviewers)

Posted by Derek

The other day, I had some uncomplimentary things to say about a recent J. Med. Chem. paper on fragment-based dihydrofo

Well, I know that I don't say these things into a vacuum, by any means, but in this case the lead author has written me abo

reviewer of the paper has showed up in the comments. So perhaps this is a topic worth revisiting?

First, I'll give Prof. Joelle Pelletier of U. Montreal the floor to make the case for the defense. Links added are mine, for backg

responsibility for t hose, and I hope they're helpful.

I was informed of your recent blog entitled How do these things get published. I am corresponding author of tha

would like to bring to your attention a crucial point that was incorrectly presented in your analysis: the target enz

that which you think it is, i.e.: it is not a DHFR that is part of a class of enzymes that's been worked on for decad

Indeed, it would make no sense to report weak and heavy inhibitors against regular DHFRs (known as type I DHF

considering the number of efficientDHFR inhibitors we already know. But this target has no sequence or st ructura

with type I DHFRs. It is a c ompletely different protein that offers an alternate path to product ion of tetrahydrofo

second page of the artic le). It has apparently evolved recently, as a bacterial response to trimethoprim being int

the environment since the 60s. Because that protein is evolutionarily unrelated to regular DHFRs, it doesnt bind

and is thus intrinsically trimethoprim resistant; it isnt inhibited by other inhibitors of regular DHFRs either. There h

efforts to date to inhibit this drug resistance enzyme, despite its increasing prevalence in clinical and veterinary s

food and wastewater (see first page of article). As a result, we know nothing about how t o prevent it from provi

resistance. Our paper is thus the first foray into inhibiting this new target one which presents both the beauty a

difficulty of c omplex symmetry.

Regular (type I) DHFRs are monomeric enzymes with an extended active-site cleft. They are chromosomally-enco

cells where they are essential for cellular proliferation. Our target, type II R67 DHFR, is carried on a plasmid, allow

dissemination between bacterial species. It is an unusual homotetrameric, doughnut-style enzyme with the partic

having a single active site in the doughnut hole. Thats unusual because multimeric enzymes typically have the sa

active sites as they do monomers. The result is that the active site tunnel, shown in Figure 4 a, has 222 symmet

front and back entrances to the active site tunnel are identical. And thats why designing long symmetrical molec

sense: they have the potential of threading through the tunnel, where the symmetry of the inhibitor would match

of the target. If they dont string through but fold up into a U, it still makes sense: the top and bottom of the tu

alike, again allowing a matc h-up of symmetry. Please note that this symmetry does create a bit of a crystallogra

nightmare at t he center of the tunnel where the axes of symmetry meet; again, it is an unusual system.

You have referred to our small, poorly documented library of fragment compounds. As for the poor documentati

that we have very little prior information on the ligands of t his new target, other than its substrates. We cast as

we could within a loosely defined chemical class, using the chemicals we have access to. Unfortunately, I dont ha

full fragment library, but am open to collaboration.

As a result of extending the fragments, the ligand efficiency does take a beating so would it have been bet ter n

it? No, that would have been dishonest. In addition, it is not a crucial point at this very early stage in discovery: t

target, and it IS important to obtain information on tighter binding, even if it comes at the cost of heavier molecu

do we pretend that these molecules are ripe for application; we have presented the first set of crude inhibitors to

inspiration for the design of the next generation of inhibitors (last sentence of the paper).

Your blog is widely read and highly respected. In this case, it appears that your analysis was inaccurate due to a

mistaken identity. I did appreciate your calm and rational tone, and hope that you will agree that there is redeem


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, .

blogs content in light of the above information, and respectfully request that you consider revising it.

Well, as for DHFRs, I'm guilty as charged. The bacterial ones really are way offthe mammalian ones - it appears that dihydro

metabolism is a problem that's been solved a number of different ways and (as is often the case) the bacteria show all kinds

the rest of the living world. And there really aren't any good D67 DHFR inhibitors out there, not selective ones, anyway, so a

would definitely be a very worthwhile tool (as well as a potential antibiotic lead).

But that brings us t o the fragments, the c hemical matter in the paper. I'm going to stand my my characterization of the frag

members is indeed small, and c laiming lack of ac cess to a "full fragment c ollection" doesn't quite cover it. Because of the am

that can be covered at these molecular weights, a 200-member library can be significantly more useful than a 100-member o

anything is more useful than a 100-member library). There aren't more compounds of fragment size on the shelves at the Un

More of a case could be made for libraries this small if they covered chemical space well. Unfortunately, looking over the list

(which is indeed in the Supplementary Material), it's not, at first glance, a very good collection. Not at all. There are some se

collection this small, mistakes are magnified. I have to point out, to start with, that compounds #59 and #81 are duplicates,

and #40, and compounds #7 and #14. (There may be others; I haven't made a complete check).

The collection is heavily biased towards carboxylic acids (which is a problem for several reasons, see below). Nearly half the

group by my quick count, and it's not a good idea to have any binding motif so heavily represented. I realize that you intent

screening set , but then, an almost featureless hydrophobic compound like #46 has no business in there. Another problem is t

compounds are so small that they're unlikely to be tractable fragment hits - I note succinimide (#102) and propyleneurea (#

there are others. At the other end of the scale, compounds such as the Fmoc derivative #25 are too large (MW 373), and th

offender in the group (nor the only Fmoc derivative). The body of the manuscript mentions the molecular weights of the coll

to 250, but there are too many outliers. This isn't a large enough collection for this kind of noise to be in it.

There are a number of reactive compounds in the list, too, and while covalent inhibitors are a very interesting field, this was focus of your efforts or as a component of the screening set. And even among these, compounds such as carbonyldiimidazol

#82, and disuccinimidylcarbonate (#36) are really pushing it, as far as react ivity and hydrolytic stability. The imine #110 is a

to have hydrolytic stability problems. Finally, the fragment #101 is HEPES, which is rather odd, since HEPES is the buffer for

Again, there isn't room for these kinds of mistakes. It's hard for me to imagine that anyone who's ever done fragment screeni

manuscript.

The approach to following up these compounds also st ill appears inadequate to me. As Dan Erlanson pointed out in a comme

Fragments post, small carboxylic acids like the ones highlighted are not always legitimate hits. They can, as he says, form ag

the assay conditions, and the most straightforward way of testing that is often the addition of a small amount of detergent,

it. The behavior of such compounds is also very pH-dependent, as I've had a chance to see myself on a fragment effort, so

that you're as close to physiological conditions as you can get. I actually have seen some of your compounds show up as hi

efforts, and they've been sometimes real, sometimes not.

But even if we stipulate that these compounds are actually hits, they need more work than they've been given. The best pra

when a fragment hit is discovered and confirmed, is to take as many closely related single-atom changes into the assay as p

group around the structure, scan a fluoro, make the N-for-C switches - at these molecular weights, these changes can make

you may well find an even more ligand-efficient structure to work from.

Now, as for the SAR development that actually was done: I understand the point about the symmetry of the enzyme, and I

the idea of making symmetrical dimer-type compounds. But, as you know, this isn't always a good idea. Doing so via flexible

is not a good idea, though, since such c ompounds will surely pay an entropic penalty in binding.

And here's one of the main things that struck both me and Teddy Z in his post: if the larger compounds were truly taking ad

symmetry, their ligand efficiency shouldn't go down. But in this case it does, and steeply. The size of the symmetical inhibito

hydrophobic regions, such as the featureless linking chains, make it unsurprising that this ef fort found some micromolar act iv

doubt show micromolar activity in such chemical space. The paper notes that it's surprising that the fragment 4c showed no

structural motif was used to build some of the more potent large compounds, but the most likely hypothesis is that this is be

have nothing to do with each other.

To be fair, compounds 8 and 9 are referred to as "poorly optimized", which is certainly true. But the paper goes on to say thpoints to develop potent and selective inhibitors, which they're not. The fragments are starting points, if they're really bindin

are dead ends. That's why Teddy Z and I have reacted as strongly as we have, because the path this paper takes is (to ou

how not to do fragment-based drug discovery.

But still, I have to say that I'm very glad to hear a direct reply to my criticism of this paper. I hope that this exchange has be

might be of use for others who read it.

Comments (24) + TrackBacks (0) | Category: Drug Assays | Infectious Diseases | The Scientific Literature

Breslow's Chirality Paper: More Than Just Alien Dinosaurs

Posted by Derek

Update: the paper has, for now, beenpulledby JACS. More to come, no doubt.


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I didn't written anything about the Breslow origins-of- chirality paper that mentioned, as a joking aside, the possibility of inte

most readers will know, the ACS publicity off ice, most cluelessly, decided to make that throwaway line the focus of their pre

confusion ensued.

But things have gotten weirder. Stu Cantrill read the Breslow paper, and realized that he'd already read a lot of it before. Se

2, 3) and realize the extent to which this latest paper was apparently a cut-and-paste job.

I've met Breslow many times (he used to consult for one of my former employers), and I've enjoyed reading much of his work

be acceptable - we wouldn't put up with it from some unknown chemist, and we shouldn't put up with it f rom someone famo

excellent summary of the situation, with recommendations about what the ACS should do next. These range from fixing that

retracting the paper, to barring Breslow from publishing in JACS for a period.

In retrospect, the alien dinosaurs are becoming my favorite part of the whole paper.

Update: Breslowdefends himselfto Nature News.


Drug Company Culture: It's Not Helping

Posted by Derek

I wanted to call attention to a piece by Bruce Booth over at Forbes. He starts off from the Scannell paper in Nature Reviews

were discussing here recently, but he goes on to another factor. And it's a big one: culture.

Fundamentally, I think the bulk of the last decades productivity decline is attributable to a culture problem. The B

culture has been homogenized, purified, sterilized, whipped, stirred, filtered, etc and lost its ability to ferment the

required to innovate. This isnt covered in most reviews of the productivity challenge facing our industry, because

impossible to quantify, but its well known and a huge issue.

You really should read the whole thing, but I'll mention some of his main points. One of those is "The Tyranny of the Committ

good can ever be decided unless there are a lot of people in the room - right? And then that decision has to move to another

give it a different working-over, with lots more PowerPoint - right? And then that decision moves up to a group of higher-lev

the slides again - or summaries of them - and make a collective decision. That's how it's supposed to work - uh, right?

Another is "Stagnation Through Risk Avoidance". Projects go on longer, and keep everyone busy, if the nasty issues aren't fa

everyone has room to deflect blame when things go wrong, if plenty of work has been poured into the project , from several

the bad news hits. Most of the time, you know, some sort of bad news is waiting out there, so you want to have yourself (a

beforehand - right? After all, several high-level committees signed off on this project. . .

And then there's "Organizational Entropy", which we've discussed around here, too. When the New, Latest, Really-Going-to-

as it does every three years or so, things slow down. They have to. And a nice big merger doesn't just slow things down, it b

juddering halt. T he cumulative effect of these things can be deadly.

As Booth says, there are other factors as well. I'd add a couple to the list, myself: the tendency to think that If This Was An

Would Be Doing It (which is another way of being able to run for cover if things don't work out), and the general human sunk

Come This Far; We Have to Get Something Out of This. But his main point stands, and has stood for many years. The resear

drug companies stands in the way of getting things done. More posts on this to follow.

Comments (36) + TrackBacks (0) | Category: Drug Industry History | Life in the Drug Labs | Who Discovers and Why

Merck Serono Cuts Back

Posted by Derek

In Geneva, the (former) headquarters of Serono. They're transferring some of the jobs, but at least 500 are gone - and the

being put out into what (from here) looks like a very unfriendly jobs market. . .


April 24, 2012

That's Some Fine Editorial Work There

Posted by Derek

Since I've mentioned the scientific publication business today, I thought I'd include this story from Retraction Watch as an e

paying for when you pay Elsevier for quality control. When's the last time you saw a paper withdrawn because it "contains no

noticed that the lead author's email contract address was at the domain "budweiser.com"?



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AstraZeneca Buys Ardea. And Who Else?

Posted by Derek

Since I've mentioned Ardea Pharmaceuticals and their gout drug RDEA594 (lesinurad) here a couple of times, I should note th

decided to put up over a billion dollars to buy the ent ire company.

It's not surprising to see AZ getting the wallet out, considering the company's overall problems, which are also, naturally, th

relentless cutbacks they've been announcing. I will not, however, endorse the following statement from the company's head

"Were building some momentum here in R&D, Martin Mackay, head of research and development, said in a telephtoday. I would be disappointed if we didnt announce further deals by the end of this year. Weve taken our hits b

turning a corner.


Harvard's Had Enough

Posted by Derek

Several readers sent along this memo from Harvard's library: they see the current price structure of scientific journals as uns

asking the faculty to help them do something about it.

The Faculty Advisory Council to the Library, representing university faculty in all schools and in consultation with

Library leadership, reached this conclusion: major periodical subscriptions, especially to electronic journals publish

historically key providers, cannot be sustained: continuing these subscriptions on their current footing is financiall

Doing so would seriously erode collection efforts in many other areas, already compromised.

They're asking faculty members to try to "move prestige" to open-access journals by favoring them for new publicat ions, and

whatever they can to get away from the current scientific publishing model. And that ties in with this post over at the Guar

are the current publishers causing a financial burden, but other burdens that may be even more of a problem:

Research, especially scientific research, thrives in an atmosphere that allows the free exchange of ideas and infor

discussion and debate are essential if the scientific method is to operate properly. Before the arrival of the intern

publishers prov ided a valuable service that was a real benefit t o the scientific community. Not any more. . .

. . .But open access isn't just about t he end products of research. It's the entire process of sc ientific enquiry, inc

collection and processing of data, scrutiny of the methods used in the analysis, questioning of assumptions, and d

alternative interpretations. In particular, it's about ac cess to sc ientific data.

I believe all data resulting from publicly funded research should be in the public domain, for two reasons. First, it's

that funds us, so we scientists have a moral responsibility to be as open as possible with the public. Second, the

method only works when analyses can be fully scrutinised and, if necessary, replicated by other researchers. In o

seek to prevent your data becoming freely available is plain unscientific.

We'll see how far this gets. But this is already the biggest upheaval that I can remember in the scientific literature, and it sho

down. . .


April 23, 2012

Making Their Own ALS DrugPosted by Derek

We should expect to see more of this sort of thing. The Wall Street Journalheadline says it all: "Frustrated ALS Patients Con

this case, the drug appears to be sodium chlorite, which is under investigation as NP001 by Neuraltus Pharmaceuticals in Pal

isn't one of their lead structures at the top of their web site).

It is an accepted part of scientific lore that sc ientists sometimes use themselves in experiments, and cancer pat

others with life-threatening illnesses are known to self-medicate using concoctions of vitamins, special teas, and

medications. But the efforts of patients with ALS to come up with a home-brewed version of a drug still in early-s

trials and not approved by the FDA is one of the most dramatic examples of how far the phenomenon of do-it-you

has gone.

A number of pat ients who have been involved in the Phase II trials of NP001 have been sharing information about it, and the

into the literature enough to be pretty sure that what Neuraltus is invest igating is, indeed, some formulation of sodium chlor


15/15


Mr. Valor first read about NP001 in a news release. He tracked down published papers that led him to believe the

sodium chlorite, a chemical that in various forms is used in municipal water treatment plants. A friend found onlin

scientists' patent filings. He also consulted an engineer in water treatment to learn more and read environmental

insight into toxicity levels. The chemical is easy to order online and is inexpensive. He estimates he has spent less

total.

Mixed in distilled water, the sodium chlorite is delivered through Mr. Valor's feeding tube three days a week, one

month. He says he cautions participants that the chemical isn't as efficacious as NP001 and "that this is only to b

NP001 is available to all."

This case is the prefect situation for something like this to happen: a terrible disease, with an unfortunately fast clinical courgood fraction of the patient population to be very organized, along with an easily-available active agent. If NP001 were som

antibody, we wouldn't be having this discussion (although eventually, who knows?) And as much as I agree that Phase II an

necessary to find out if something really works or not, if I had ALS myself, I'd be doing what these people are doing, and if it

affected, I'd be helping them mix the stuff up. With a condition like ALS, honestly, the risk/benefit ratio is pretty skewed.

If NP001 progresses, look for comment along the lines of "How can this little company get a patent on the use of this commo

disease?" But as the WSJarticle reports, the sodium chlorite mixtures that people are whipping up in their kitchens don't see

whatever NP001 is, for one thing. And Neuraltus is basically much of their existence on whether it works or not; they're takin

of a proper investigation, and good for them. But it's true that many people who have ALS right now will not be around to se

trial, and I can't blame them at all for doing whatever they can to try to get some of the benefits of this research in the inte

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